Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson's disease

The pathologic accumulation and aggregation of alpha-synuclein (alpha-syn) underlies Parkinson's disease (PD). The molecular mechanisms by which pathologic alpha-syn causes neurodegeneration in PD are not known. Here, we found that pathologic alpha-syn activates poly(adenosine 5'-diphosphate-ribose) (PAR) polymerase-1 (PARP-1), and PAR generation accelerates the formation of pathologic alpha-syn, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP-1 prevented pathologic alpha-syn toxicity. In a feed-forward loop, PAR converted pathologic alpha-syn to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with PD, suggesting that PARP activation plays a role in PD pathogenesis. Thus, strategies aimed at inhibiting PARP-1 activation could hold promise as a disease-modifying therapy to prevent the loss of dopamine neurons in PD.